Enantioselective catalysis in fine chemicals production

Applied Catalysis A: General 221 (2001) 119–143

Enantioselective catalysis in fine chemicals production H.U. Blaser∗ , F. Spindler, M. Studer Solvias AG, Postfach, CH-4002 Basel, Switzerland

Abstract This review describes the state of the art for the application of enantioselective catalysts for the industrial production of enantiomerically enriched chiral fine chemicals. In a certain sense it is an up-date of an overview written by Scott 10 years ago [1]. A comparison of the two articles reveals that certain aspects such as the difficulty to get precise information on industrial processes remained the same. As a consequence, many references relate to relatively informal sources such as C&EN, proceedings of commercial meetings and reviews. Other aspects, especially the state of the art in enantioselective catalysis but also the nature of the industrial players have changed significantly in the last decade. The present overview tries to cover all enantioselective catalytic processes that have been and/or still are used for the commercial manufacture of enantioenriched intermediates. In addition, we have also tried to get information on catalytic processes not (yet) used in actual production. Another goal of the review is to give the organic chemist working in process development an impression of the synthetic opportunities of enantioselective catalysis and to impart to the production manager some understanding of the potential problems when enantioselective processes are developed. After a short introduction to the world of chirality and enantioselective catalysis, the most important production methods for enantiopure chiral molecules are described. The relevant requirements for the application of enantioselective catalysis in fine chemicals production are then discussed in order to show what factors determine whether a catalytic method can be applied successfully or not. In the next paragraphs, the major industrial players in the field of enantioselective catalysis, existing processes in production and selected examples of processes in the bench scale and pilot stage are described. In a similar way, large scale ligands and chiral auxiliaries for enantioselective catalysis and their producers are tabulated and described. © 2001 Elsevier Science B.V. All rights reserved. Keywords: Enantioselective catalysis; Industrial processes; Chiral ligands; Asymmetric hydrogenation; Process development

1. Chirality and its impact on chemistry [2] In 1848, Louis Pasteur discovered that two tartaric acid molecules with otherwise identical properties differed in the sign of their optical rotation. This fundamental discovery was the basis for the development of stereochemistry in general and the phenomenon of “chirality” in particular, with far-reaching implications in organic and biochemistry. Very soon Pasteur recognized the tendency of living systems to produce chiral ∗ Corresponding author. Tel.: +41-61-686-61-55. E-mail address: [email protected] (H.U. Blaser).

molecules (he called them dissymetric) not as racemic (50:50) mixtures but enantiomerically pure (100:0). In addition, he correctly stated that enantiomerically pure (or enantioenriched) compounds can only be produced artificially in the presence of a physical or chemical chiral agent (in the case of the tartrate, this agent was Pasteur himself, who manually separated the left and the right handed crystals). Soon it was also realized that the biological activity of the two enantiomers can differ considerably, e.g. natural l-asparagine is bitter, whereas artificial d-asparagine is sweet. Even though all important elements of chirality in the context of man-made compounds were known, it took many

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more years until topics such as asymmetric synthesis, enantioselective catalysis or “single isomer drugs” left the status of curiosities and became central issues in academia and in the life science industry. Today, pharmaceuticals and vitamins [3–5], agrochemicals [6], flavors and fragrances [6,7] but also functional materials [8,9] are increasingly produced as enantiomerically pure compounds. The reason for this is the often superior performance of the pure enantiomers and/or because regulations demand the evaluation of both enantiomers of a biologically active compound before its approval. This trend has made the economical enantioselective synthesis of chiral performance chemicals a very important topic. 2. Preparation methods for enantiopure chiral molecules Chiral molecules such as pharmaceuticals or agrochemicals usually have complex, multifunctional structures and are produced via multistep syntheses. Compared to basic chemicals, they are relatively small scale but high value products with short product lives, traditionally produced in multipurpose batch equipment. The time for development of the production process is often very short since “time to market” affects the profitability of the product [10,11]. Four general approaches for producing enantiopure (e.e. >99%) or enantioenriched compounds economically have evolved [12] (see Table 1 for a comparison of the different methodologies and our personal assessment concerning their suitability for industrial applications).

1. Separation of enantiomers via classical resolution, i.e. crystallization of diastereomeric adducts is still responsible for >50% of enantioenriched drugs [13]. In the emerging stage is separation on chiral HPLC using moving simulated bed technology [14]. While crystallization of diastereomeric adducts can be applied on any scale, separation via high performance liquid chromatography (HPLC) is probably most important in the early phase of product development and restricted to small scale (100 kg to t), high value products. In both cases, large amounts of solvents have to be handled and of course at least 50% of the material with the wrong absolute configuration has to be either recycled or discarded. 2. The chiral pool approach, i.e. the use of chiral building blocks originating from natural products for the construction of the final molecule. This approach is very often used in early phases of drug development but depending on the commercial availability of the starting material, it can also be used on large scale products. Because natural products very often (but not always!) have high enantiomeric purity, no further enrichment is usually necessary. 3. Use of enzymatic and microbial transformations, i.e. in many respects, one must deal with similar problems as for chemical catalysts as due to problems occuring it can take a long time finding and developing an efficient biocatalyst, especially when the starting material is not a very close analog to the natural substrate, and the product isolation from an often rather dilute aqueous solution.

Table 1 Scope and limitations of major production methods for enriched chiral moleculesa

Enantioselectivity Activity, productivity Availability, diversity Substrate specificity Work-up, ecology Development time, effort Application in the lab Application in development Small scale production Large scale production a

Catalysis

Biocatalysis

Chiral pool

Resolution

HPLC

1–2 1–2 1–2 2 1–2 2 2 1–2 1–2 1

1 2–3 2–3 3 2–3 3 3 2 1–2 2–3

1 – 2 1 2 1 1 1 1 2

1–2 – 1 1 2 1–2 1–2 2 1–2 1–2

1 – 1 2 2 1 1 2 2 3

Rating: 1: high, 2: medium, some problems, 3: low, problematic.

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4. Enantioselective syntheses with the help of chiral auxiliaries (originally also from the chiral pool) that are not incorporated in the target molecule but either lost or recycled. The most attractive variant of this approach is of course enantioselective chemical catalysis where the expensive chiral auxiliary is used in catalytic amounts (Table 1).

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mers never gained any practical importance, Akabori et al.’s [20] observation that Pd deposited on silk fibroin was able to hydrogenate a C=C bonds with e.e. up to 66% gave new hope to the then fledgling field of enantioselective catalysis (even though this result turned out to be unreproducible!). The first successful examples (albeit with very modest e.e.) of homogeneous chiral metal complexes were reported in 1966 and 1968 by the groups of Nozaki et al. [21], Horner et al. [22] and Knowles and Sabacky [23]. But the e.e. improved very rapidly and especially the successful development of the Rh-dipamp catalyst for the l-dopa process at Monsanto with e.e. up to 95% stimulated the catalytic community tremendously (see below). Today, enamides are still used as standard test substrates for many new ligands. The next two milestones followed quickly with Katsuki and co-workers epoxidation [24,25] and the synthesis of the binap ligand [26]. The Sharpless and Katsuki epoxidation developed to be of very high preparative value for the synthetic chemist, binap turned out to be the most versatile ligand ever developed (Table 2). Further progress in the eighties and nineties was rapid on a broad front and it is not easy to distinguish one or two especially significant catalysts or reactions. A very good overview can be found in the recent monograph Comprehensive Asymmetric Catalysis by Jacobsen Yamamoto and Pfaltz [27]. A few personal favorites: Os-cinchona catalyzed dihydroxylation [24], epoxidation of unfunctionalized olefins with Mn-salen catalysts [28], allylic substitution with various Pd catalysts [29], duphos ligands [30], Ir-ferrocenyldiphosphine complexes for C=N hydrogenation (Ciba-Geigy/Solvias) [31,46].

3. Scientific developments in enantioselective catalysis [2,15] Over the years, many different approaches to obtain enantioselective catalysts were tried, but only very few were really successful. A major problem was the determination of the enantioselectivity, measured via optical rotation (called optical yield, defined as % “desired”–% “undesired” enantiomer); now the same numbers are called enantiomeric excess (e.e.). Especially in the early years, optical yields were very low or not even determined quantitatively but at that time, the proof of concept for a particular approach was more important. Table 2 represents a (rather subjective) list of scientific milestones in the history of enantioselective catalysis, starting with the first known example, the quinine catalyzed addition of HCN to benzaldehyde described by Bredig and Fiske in 1912 [16], establishing the first proof of concept for asymmetric chemical catalysis. In 1940, Nakamura [17] was the first to use chiral auxiliaries to modify a heterogeneous catalyst. This approach culminated at the end of the seventies in the development of the only synthetically useful heterogeneous chiral catalysts, tartrate modified nickel [18] and cinchona modified platinum [19] catalysts. Although the application of chiral biopolyTable 2 Early scientific milestones in enantioselective catalysis up to 1980 Year

Milestone

Chiral catalyst

e.e. (%)

Reference

1912 1940 1956 1966 1968 1978 1979 1980 1980

HCN addition to PhCHO Hydrogenation of C=N Hydrogenation of C=C Cyclopropanation Hydrogenation of enamides Hydrogenation of ␤-keto esters Hydrogenation of ␣-keto esters Epoxidation of allylic alcohols Binap ligand

Quinine Chiral acid on Pt black Pd on silk fibroin Cu-Schiff’ base complex Rh chiral phosphine Ni-tartrate-NaBr Cinchona alkaloids on Pt Ti-tartrate complex Rh, Ru complexes

<10 18 66 10 <15 89 >80 >90 High

[16] [17] [20] [21] [22,23] [18] [19] [25] [26]

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Over the years, three types of enantioslective catalysts have proven to be synthetically useful. The most versatile are homogeneous metal complexes with chiral ligands. The most common ligands are bidentate, i.e. have chiral backbone with two coordinating heteroatoms. For noble metals, especially Rh, Pd, Ru and Ir, these are usually tertiary P or N atoms, for the early transition metals such as Ti, B or Zn, ligands with O or N coordinating atoms are preferred. Also useful for synthetic application are heterogeneous metallic catalyst, modified with chiral auxiliaries and finally chiral soluble organic bases or acids. Less easy to apply are chiral polymeric and gel-type materials, phase transfer catalysts or immobilized complexes. At the moment, several lines of academic research are very active [32]: design of new, more effective chiral ligands/catalysts both for existing and new transformations, combinatorial ligand preparation, high through put screening methodologies. In one short sentence: much has been achieved, even more remains to be done—but the challenge is being taken up.

4. Problems for the application of enantioselective catalysis on a technical scale Despite the dramatic progress in the scientific domain, relatively few enantioselective catalytic reactions are used on an industrial scale today (see next chapter). A major reason for this fact is that the application of enantioselective catalysts on a technical scale presents some very special challenges and problems [11,12]. Some of these problems are due to the special situation for manufacturing chiral products, others are due to the nature of the (enantioselective) catalytic process. Whether a synthetic route containing an enantioselective catalytic step can be considered for a particular product is usually determined by the answer to two questions. • Can the costs for the overall manufacturing process compete with alternative routes? • Can the catalytic step be developed in the given time frame? Several critical factors determine the technical feasibility of an enantioselective process step [11] but it

has to be stressed that even if all these criteria are met this is no guarantee that it is actually used! (see also Chapter 6). 4.1. Catalyst performance The enantioselectivity (expressed as e.e. %) of a catalyst should be >99% for pharmaceuticals if no purification is possible; e.e. >80% are often acceptable for agrochemicals or if further enrichment is easy. The catalyst productivity, given as turnover number (ton = mol product/mol catalyst) or as substrate/catalyst ratio (s/c), determines catalyst costs. For hydrogenation reactions ton’s ought to be >1000 for high value products and >50,000 for large scale or less expensive products (catalyst re-use increases the productivity). The catalyst activity given as average turnover frequency (tof = mol product/mol catalyst/reaction time, h−1 ), affects the production capacity. For hydrogenations, tof’s ought to be >500 h−1 for small and >10,000 h−1 for large scale products. Due to lower catalyst costs (see below) and often higher added values, lower ton and tof values are acceptable for enantioselective oxidation and C–C bond forming reactions. In Chapter 6, values for e.e., ton and tof are given for all processes described (if available). 4.2. Availability and cost of the catalyst Chiral ligands and many metal precursors are expensive and/or not easily available. Typical costs for chiral diphosphines are US$ 100–500/g for laboratory quantities and US$ 5000 to >20,000/kg on a larger scale. Chiral ligands such as salen or amino alcohols used for early transition metals are usually much cheaper. At this time, only selected chiral ligands are available commercially (see Chapter 7). The development time can be a hurdle, especially when the optimal catalyst has to yet be developed or no commercial catalyst is available for a particular substrate (substrate specificity) and/or when not much is known on the desired catalytic transformation (technological maturity). When developing a process for a new chemical entity (NCE) in the pharmaceutical or agrochemical industry, time restraints can be severe (see Fig. 1). In these cases it is more important to find a competitive process on time than an optimal process too late. For so-called second generation

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Fig. 1. Development process for a new chemical entity in the pharmaceutical industry.

processes, chiral switches (for existing products now sold as racemates) or other products the time factor is often not so important but here, the process must be optimal. In addition, many other aspects have to be considered when developing a catalytic reaction for industrial use: catalyst separation, stability and poisoning; handling problems; space time yield; process sensitivity; toxicity of metals and reagent; safety aspects as well as the need for high pressure equipment. 5. The players in industrial enantioselective catalysis As far as we are aware, industrial interest in the application of enantioselective catalysts started in earnest in the mid-sixties when the first publications of successful enantioselective transformations using homogeneous metal complexes were published. Within a surprisingly short period, production processes for two small scale products were developed and implemented by Monsanto and Sumitomo. For quite some time it was not really clear whether these applications where mere curiosities or whether this would be the beginning of a new area of producing chiral compounds. One reason for this state of affairs was that both companies were very reluctant to disclose much information on the new technology. Very soon some other chemical and pharmaceutical companies entered the field with an appreciable research effort. Examples are Roche, Ciba-Geigy, Takasago, Enichem or VEB-Isis-Chemie. Some worked in collaboration with academic laboratories,

other relied on strong in-house research efforts. As pointed out at the beginning of this paper, lack of information is still an obstacle for a good assessment of the scope and limitation of industrial processes but the situation is improving slowly. One reason for this improvement is the fact that in the last few years, a new type of player has entered the field: smaller companies more or less exclusively dedicated to the development and application of enantioselective processes to manufacture enriched chiral intermediates and products. Many of these enterprises are either start-up’s such as ChiRex or Oxford Asymmetry, concentrating on a few promising technologies or spin-off’s from a large corporation such as our own company, Solvias, or NSC Technologies, usually with a broader technology base. Because these companies want to sell their services and processes, they are much more willing to describe details of their catalysts and processes in order to convince prospective customers of their abilities and competence. In the following list these major players are recorded with a short (hopefully objective) description of their activities and major accomplishments. 5.1. Major pharmaceutical or integrated chemical companies Bayer: development of proprietary binap analogs. Ciba-Geigy/Novartis: early research in enantioselective hydrogenation; application to selected agrochemical and pharmaceutical products. Proprietary ligand family; several production, pilot and bench scale processes. Activities have been spun-off into Solvias AG (see below).

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DuPont: strong research effort in enantioselective catalysis, proprietary ligand class (partially transferred to ChiroTech). HöechstMarionRoussel/Aventis (HMR/A): application of known technology to selected products. Several pilot and bench scale processes. Hoffmann-La Roche (Roche): strong and early efforts to integrate enantioselective catalytic steps in the synthesis of chiral vitamins, fine chemicals and pharmaceuticals. Development of a proprietary family of biphenyl diphosphine ligands (bipheps); many pilot and bench scale processes. Ligands licensed to PPG-Sipsy. Merck: strong efforts to integrate enantioselective catalytic steps in the synthesis of chiral new chemical entities. Several pilot and bench scale processes, proprietary ligand. Monsanto: pioneer in the application of enantioselective hydrogenation; first chiral diphosphine ligand (dipamp) with high enantioselectivity. Application to selected products. Activities have been transferred to NSC Technologies, now part of Great Lakes Fine Chemicals. Sepracor: strong efforts to integrate enantioselective catalytic steps in the synthesis of chiral new chemical entities. Several pilot and bench scale processes, proprietary ligand. SmithKline Beecham (SKB): application of known technology to selected products. 5.2. Chemical companies or custom manufacturers Arco: first commercial application of the Sharpless epoxidation. One production process (licensed to PPG-Sipsy). Degussa-Hüls: early efforts to develop technology for enantioselective hydrogenation. One proprietary ligand (deguphos), license for proprietary ligands; one pilot process. Enichem/Anic: application of known technology to selected products. One production process. Lonza: application of known technology to selected products. One production process, several pilot and bench scale processes. Rhone-Poulenc/Rhodia: some efforts to develop enantioselective catalysis. Proprietary ligand. Sumitomo: early effort in applying Cu catalyzed cyclopropanation in production process.

Takasago: early and strong efforts in developing the potential of the binap ligand for isomerization and hydrogenation. Proprietary binap ligand family. Several production and pilot processes. VEB-Isis-Chemie: application of known technology to selected products. Proprietary ligand (glup) and one production process (abandoned). 5.3. Specialized companies (especially start-up’s or spin-off’s) Catalytica: license for proprietary ligands. Chemi S.p.A.: application of known technology to selected products. Some efforts to develop enantioselective catalysis. Proprietary ligands (TMBTP and analogs). Some pilot and bench scale processes. ChiRex: technical development of several licensed catalyst systems, several productions, pilot and bench scale processes. ChiroTech: technical development of several licensed catalyst systems, several pilot and bench scale processes. NSC Technologies (now part of Great Lakes Fine Chemicals): proprietary ligand family (see Monsanto), several production and pilot processes. Oxford Asymmetry: strong efforts in enantioselective synthesis. Immobilized binap ligand. PPG-Sipsy: application of various technologies to selected products; several production and pilot processes, license for several catalyst systems. Solvias: license for several catalyst systems (see Ciba-Geigy/Novartis).

6. Industrial enantioselective catalytic processes Since the first production process have been implemented by Monsanto and Sumitomo in the early seventies, the list has grown only slowly and comprises today about 15 entries. This number is fraught with uncertainties because many companies are very reluctant to disclose information on their manufacturing processes. Paradoxically, we often know more about abandoned or potential catalytic processes than about those that are really in operation because it is often easier to publish when a process is not in operation. Fifteen operating processes are not very impressive, especially since several of

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Table 3 Statistics for the various types of processes Transformation

Production

Pilot

Bench scale

Hydrogenation of enamides Hydrogenation of C=C–COOR and C=C–CH–OH Hydrogenation of other C=C systems Hydrogenation of ␣-functionalized ketones Hydrogenation of ␤-ketoesters Hydrogenation/reduction of other keto groups Hydrogenation of C=N Dihydroxylation of C=C Epoxidation of C=C, oxidation of sulfide Isomerization, epoxide opening, addition reactions

3 1 1 2 2 – 1 – 4 2

8 8 3 5 5 1 1 1 2 3

4 6 2 3 1 4 – 4 2 1

them have been used for only a short time (and then stopped) and since most are still relatively small scale. However, the isomerization process of Takasago and the (S)-metolachlor hydrogenation process of Ciba-Geigy/Syngenla demonstrate that enantioselective homogeneous catalysis is not restricted to small tonnages but is also a feasible technology for quite large volume products. In addition, many of the 35 reactions classified as pilot processes and also some of the bench scale processes are extremely efficient

and in a way should be added to this list. Many perfectly viable and competitive catalytic processes are not operated for a variety of reasons unrelated to the catalytic step; sometimes because the overall-route is not competitive, sometimes because an older process is in operation (in written-off equipment) and investment would be too high to change to the new, more efficient process, and sometimes because the product was abandoned, e.g. due to toxicological problems.

Fig. 2. Hydrogenation of C=C bonds; structures of starting materials listed in Table 10.

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Fig. 3. Hydrogenation of C=O bonds; structures of starting materials listed in Table 11.

Fig. 4. Oxidation of C=C bonds and addition to C=O bonds; structures of starting materials listed in Table 12.

Fig. 5. Structure of naproxen and starting materials.

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Table 4 Production processes: hydrogenation of C=C bondsa

Monsanto [33–35]: intermediate for l-dopa (Parkinson); scale ca. 1 t per year Success factors: ligand design, solvent, crystallization (separation of catalyst and racemate) Critical issues: oxygen, peroxides in reaction solution, synthesis of enamide

VEB-Isis-Chemie [36–38]: intermediate for l-dopa (Parkinson); scale ca. 1 t per year (production terminated) Success factors: ligand design, air stable ligand, sulfate anion Critical issues: oxygen concentration, synthesis of enamide

Enichem/Anic [1,39,40]: intermediate for aspartame (sweetener); ca. 15 t produced (production terminated) Success factors: easy ligand preparation, recrystallization Critical issues: stability of ligand (P–N bond)

Takasago [41–43]: citronellol and intermediate for Vitamin E; scale 300 t per year Success factors: Ru precursor, anion, catalyst filtration possible, high chemoselectivity

Lonza [44,45]: intermediate for biotin (vitamin); multi t scale (production terminated) Success factors: ligand type and fine tuning Critical issues: catalyst activity and productivity, efficient synthesis of starting material a For

structures of ligands, see Figs. 6 and 7.

In Tables 4–12, we have divided the processes in three classes according to their development stage. • Production processes, which are operated on a more or less continuos basis, i.e. where all relevant problems concerning catalyst performance and sep-

aration, supply of materials, product isolation and purification, noble metal recovery, etc. have been solved. • Pilot processes, where the catalyst performance is sufficient for commercial production and where the most technical important problems have been solved.

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Fig. 6. Ligand (families) with axial chirality: short names and structures.

• Bench scale processes, where the catalyst performance has been optimized to various degrees but which for some reason are not yet ready for production.

Furthermore, the processes have been sorted according to the catalytic transformation. If available, the following informations for each process are given: company, structures of substrate and product, use of

Fig. 7. Various types of diphosphine ligands: short names and structures.

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Table 5 Production processes: hydrogenation of C=N and C=O bondsa

Ciba-Geigy/Syngenla (Solvias) [44,47]: intermediate for (S)-metolachlor herbicide (Dual Magnum® ), >10000 t per year Success factors: Ir catalyst, ligand type and ligand tuning, iodide/acid addition Critical issues: impurities

Ciba-Geigy(Solvias) [48]: intermediate for benazepril and other prils (ACE inhibitors); multi t scale (production terminated) Success factors: catalyst and modifier tuning, existing analogy, reaction conditions, solvent (92% e.e. in AcOH) Critical issues: substrate synthesis and quality

Takasago [41]: intermediate for (S)-oxfloxazin (bactericide, chiral switch); 50 t per year

Takasago [41,42,49]: intermediate for carbapenem (antibiotic); 50–120 t per year Success factors: dynamic kinetic resolution, ligand fine tuning

NSC Technologies [50]: chiral building blocks, three derivatives; hundreds of kilogram (one small scale production, two pilot processes) a For

structures of ligands, see Figs. 2 and 3.

final product, catalyst (metal complex, chiral ligand or auxiliary), e.e., ton and tof of the catalyst, reaction temperature and pressure, scale, success factors and critical issues. 6.1. Some comments on the various processes An analysis of Tables 4–12, shows that hydrogenations are by far the predominant transformations that have successfully been developed to industrial processes, followed by epoxidation and dihydroxylation

reactions (see Table 3). On the one hand, this is due to the broad scope of catalytic hydrogenation and on the other hand it could be attributed to the early success of Knowles with the l-dopa process, because for many years after most academic and industrial research was focused on this transformation. The success with epoxidation and dihydroxylation can essentially be attributed to the efforts of Sharpless, Katsuki and Jacobsen. If one analyzes the structures of the starting materials in Tables 4–12, it is quite obvious that many of these are quite complex, multifunctional

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Table 6 Production processes: various transformations (isomerization, epoxidation, cyclopropanation, addition and sulfoxidation)a

Sumitomo [52,53]: intermediate for cilastatin (dehydropeptidase); small scale Success factors: ligand design and optimization Critical issues: preparation and handling of diazo compound

Takasago [41,42,54]: intermediate for l-menthol (>1000 t per year); hydroxy-dihydro-citronellal (40 t per year); d- and l-citronellol (20 t per year); methoprene juvenile hormone (20 t per year) Success factors: choice of Rh, ligand design, Rh precursor, catalyst recycling, substrate purification (vitride, distillation), chemoselectivity Critical issues: catalyst productivity, sensitivity towards amines, O2 , H2 O, CO2

J.T. Baker [1]: intermediate for disparlure (pheromone); small scale Remark: first industrial application of Sharpless technology Critical issues: low temperature, high catalyst loading

PPG-Sipsy [55]: chiral building block; multi t per year Success factors: molecular sieves, reaction conditions Critical issues: isolation of product, removal of hydroperoxides

Merck/ChiRex (Sepracor) [56–58]: intermediate for crixivan (HIV protease inhibitor) and ligand for BH3 reduction; small scale Success factors: solvent, addition of 3-phenylpropyl pyridine N-oxide (P3 NO), ligand synthesis Critical issues: ligand stability, pH control for NaOCl stability and availability

AstraZeneca [59–61]: esomeprazole (anti-ulcer) multi t scale Success factors: choice of cumene hydroperoxide as oxidant, addition of Hünig base and water, generation of catalytic species in presence of substrate Critical issues: over-oxidation to sulfone, high catalyst loading (process stability and robustness, e.e.), substrate purity, chemical yield and e.e. a For

structures of ligands, see Figs. 6 and 8.

H.U. Blaser et al. / Applied Catalysis A: General 221 (2001) 119–143 Table 7 Pilot processes: hydrogenation of C=C bondsa

Degussa-Hüls [62]; intermediate for aspartame (sweetener); multi 10 kg scale Success factors: new ligand type, catalyst recycle possible

HöchstMarionRoussel/Aventis [63]: intermediate 2 for HMR 2906 (factor Xa: inhibitor); multi 10 kg scale Success factors: increase of e.e. from 98.5 to >99.8% by precipitation from reaction mixture Critical issues: oxygen concentration, purity of starting material

ChiroTech [64]: pharmaceutical intermediate; >200 kg produced Success factors: large scale ligand synthesis, acid addition Critical issues: catalyst inhibition by pyridyl N

HöchstMarionRoussel/Aventis [63]: intermediate 1 for HMR 2906 (factor Xa: inhibitor); multi 10 kg scale Success factors: presence of HBF4 , low H2 -pressure, ligand fine tuning, increase of e.e. to >99% by single recrystallization (after deacetylation and Cbz-protection) Critical issues: oxygen concentration, solubility of starting material

Ciba-Geigy/Syngenla (Solvias) [65]: intermediate for (R)-metalaxyl (fungicide); kg scale Success factors: ligand screening, optimization of reaction conditions Critical issues: synthesis of starting material

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Table 7 (Continued)

ChiroTech (for Nycomed) [66]: pharmaceutical intermediate; multi kg scale Success factors: dienamide synthesis via dialdehyde Critical issues: substrate purity

Lonza [45,67]: building block for pharmaceuticals; >200 kg produced Success factors: ligand type and fine tuning, substituents at tetrahydropyrazine Critical issues: catalyst productivity, efficient synthesis of starting material

Roche [68,69]: intermediate for cilazapril (HIV protease inhibitor); multi 10 kg scale Success factors: ligand type and fine tuning, NEt3 addition Critical issues: substrate purity

Roche [68]: citronellol and intermediate for Vitamin E, multi 10 kg scale

Takasago [42]: intermediate for Vitamin E; multi kg scale Success factors: Ru precursor, anion Critical issues: E/Z ratio in substrate

Roche [68]: intermediate for Vitamin E, kg scale

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Table 7 (Continued)

Roche [68–70]: intermediate for mibefradil (calcium antagonist); multi 10 kg scale (batch mode: 20 ◦ C, 180 bar; e.e. 94%; ton: 8000; tof >800 h−1 ) Success factors: type of diphosphine, ligand fine tuning, NEt3 addition, continuous mode reaction (residence time 2 × 75 min) Critical issues: very high pressure (affects e.e.), catalyst activity (tetrasubstituted C=C)

ChiroTech (for Pfizer) [71]: intermediate for candoxatril (anti-hypertensive); multi 100 kg scale Success factors: type of ligand, ligand tuning, catalyst precursor, reaction conditions (pressure) Critical issues: isomerization of C=C, impurities

PPG-Sipsy (for Pfizer) [72]: intermediate for candoxatril (anti-hypertensive); multi 100 kg scale Success factors: type of catalyst, solvent, reaction conditions Critical issues: patent situation for Ru-binap

Chemi S.p.A. [73]: intermediate, multi 100 kg scale Success factors: new ligand

ChiroTech [74]: pharmaceutical intermediate; multi kg scale Success factors: addition of base co-catalyst, E/Z mixture of substrate tolerated

ChiroTech (for Pharmacia & Upjohn) [64,75]: intermediate for tipranavir; ‘production scale’ Success factors: Na2 CO3 co-catalyst, E/Z mixture of substrate tolerated, chemoselectivity Critical issues: nitro group over-reduction

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Table 7 (Continued)

Firmenich [76]: (+)-cis-methyl dihydrojasmonate (perfume); multi 100 kg scale (production planned) Success factors: Ru precursor, ligand type, solvent, additives, chemo- and cis-selectivity Critical issues: catalyst productivity, quality of starting material

Roche [69]: intermediate for zeaxanthin (natural pigment); multi kg scale Success factors: type of diphosphine, structure of substrate, addition of catalyst, chemoselectivity Critical issues: regioselectivity, exothermicity, substrate impurities a For

structures of ligands, see Figs. 6 and 7. Scale is usually given as the overall amount produced.

Table 8 Pilot processes: hydrogenation/reduction of C=N and C=O bonda

Lonza [44,67]: intermediate for dextromethorphan (antitussive); >100 kg produced Success factors: Ir catalyst, ligand type and fine tuning, biphasic system, additives, chemoselectivity Critical issues: catalyst productivity, quality of starting material

Roche [68]: intermediate for pantothenic acid (vitamin); multi 100 kg scale Success factors: good analogy, ligand fine tuning, anion, synthesis of starting material Critical issues: purity of substrate, solvent and hydrogen

Solvias (for Ciba LSM) [77]: intermediate for benazepril and related prils (ACE inhibitors); multi 10 kg scale Success factors: catalyst and modifier tuning, existing analogy, reaction conditions, solvent, single crystallization gives e.e. >99%, low cost overall route, chemoselectivity Critical issues: substrate synthesis and quality

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135

Table 8 (Continued)

Ciba-Geigy (Solvias) [78]: levoprotiline (anti-depressant); multi 10 kg scale Success factors: good analogy, reaction conditions, large scale ligand synthesis, crystallization of product Critical issues: impurities

Sepracor [79–81]: intermediate for (R,R)-formoterol (␤2 -agonist); multi kg scale

PPG-Sipsy (with Callery) [82,83]: pharmaceutical building block, commercial quantities

Roche [68,84]: intermediate for orlistat (obesity); 10 kg scale Success factors: ligand fine tuning, reaction conditions, crystallization of product (e.e. >99%)

Roche [68,84]: intermediate for orlistat (obesity); t scale Success factors: easy separation and recycling of catalyst, crystallization of product (e.e. >99%) Critical issues: catalyst preparation, catalyst e.e. and activity, decrease of e.e. with recycling (91 → 84%)

HöechstMarionRoussel/Aventis [85,86]: essential building block for HMG-CoA reductase inhibitors (cholesterol lowering); 10 kg scale Success factors: carefully distilled starting material, in situ catalyst, granted patents for the overall process and specific process step Critical issues: oxygen concentration

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Table 8 (Continued)

Merck [87]: intermediate for BO-2727 (antibiotic); multi kg scale Success factors: phosphine, optimization of reaction conditions, HCl addition Critical issues: purity of starting material, availability of ligand

Chemi S.p.A. [73]: intermediate, multi 100 kg scale Success factors: new ligand

Lonza [88,89]: intermediate for josiphos ligands; 50 kg produced a For

structures of ligands, see Figs. 6–8. Scale is usually given as the overall amount produced.

Table 9 Pilot processes: isomerization, epoxidationa

ChiRex [28]: chiral building blocks; multi 100 kg scale Success factors: catalyst recycling possible, separation of products via fractional distillation Critical issues: amount of water

ChiRex [90,91]: chiral building block; multi 10 kg scale

Upjohn [92]: intermediate for disparlure (pheromone); multi 10 kg scale Success factors: molecular sieves, high olefin concentration Critical issues: low temperature, high catalyst loading

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137

Table 9 (Continued)

Roche [68,93]: intermediate for trocade (collagenase inhibitor); multi 100 kg scale Success factors: addition of molecular sieves Critical issues: water content of molecular sieves (6–10%)

Lonza [1,88,94]: building block for pharmaceuticals; scale >100 kg

Lonza [67,88]: building block for pharmaceuticals; <100 kg scale a For

structures of ligands, see Figs. 2 and 4. Scale is usually given as the overall amount produced.

Table 10 Bench scale processes: hydrogenation of C=C bondsa Company

Transformation use

Catalyst

e.e. (%)

Ton

Tof (h−1 )

Reference

HMR/A HMR/A HMR/A HMR/A Takasago Roche Takasago Merck Roche Roche Roche Roche Roche

C=C–COOH 2.1 HBY 793 (HIV protease inhibitor) C=C–COOH 2.2 HOE 140 (Bradykinin antagonist) Enamide 2.3 CRC 220 (thrombin antagonist) C=C–COOH 2.4 S2864 (renin inhibitor) Cyclic enamide 2.5 dextromethorphan (antitussive) Cyclic enamide 2.6 dextromethorphan (antitussive) Diketene 2.7 monomer, biodegradable polymer Cyclic enamide 2.8 L-692, 429 (hormone secretagogue) Trisubstituted C=C 2.9 Vitamin E Cyclic O–C=C 2.10 orlistat (obesity) C=C–COOR 2.11 Ro 42-5892 (renin inhibitor) C=C–CH2 –OH 2.12 (S)-fenpropidine (kinase inhibitor) Cyclic C=C–CH2 –OH 2.13

Ru/binap Rh/bpm2 Rh/bpm2 Rh/deguphos2 Ru/binap Ru/biphep2 Ru/binap Ru/binap Ru/biphep4 Ru/biphep7 Ru/biphep5 Rh/tolbinap Rh/biphep3

65 99 92 86 98 98 92 82 94 96 88 96 98

500 1600 ∼1100 200 1000 20000 1000 n.a. 1000 2000 1000 20000 5000

∼10 1600 ∼45 ∼10 300 6600 200 n.a. 45 40 40 800 200

[85,86] [85,86] [85,86] [85,86] [41] [68] [41,42] [87] [68,95] [69,95] [84] [96] [96]

a For

structures of starting materials see Fig. 2, for structures of ligands see Figs. 6 and 7.

Table 11 Bench scale processes: hydrogenation and reduction of C=O bondsa Company

Transformation use

Catalyst

e.e. (%)

Ton

Tof (h−1 )

Reference

Eli Lilly Takasago Roche Roche Roche Roche Sepracor

Thioph-C=O reduction 3.1 LY300502 (serotonin inhibitor) ␤-Ketoester 3.2 monomer, biodegradable polymer ␣-Ketoester 3.3 Ro 40-2148 (obesity) ␣-Aminoketone 3.4 Ro 40-2148 (obesity) ␤,␥-Unsaturated-␣-ketoacid 3.5 cilazapril (ACE inhibitor) Ar-CO-Ar 3.6 mefloquine (anti-malarial) Ar-CO-R 3.7 (S)-fexofenadine (antihistamine)

Aminol/LiAlH4 Ru/binap Ru/biphep3 Ru/biphep3 Rh+ /bppfoh Ru/biphep6 Indan/BH3

90 99 93 97 87 92 90

Stoich. 5000 2000 3000 2000 6400 20

n.a. 600 100 100 90 320 10

[97] [42] [84] [84] [84] [69,95] [98,99]

a For

structures of starting materials, see Fig. 3, for structures of ligands, see Figs. 6–8.

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Table 12 Bench scale processes: isomerization, epoxidationa Transformation use

Catalyst

e.e. (%)

HMR/A

Cyclic C=C dihydroxylation 4.1 chiral building block Ar-C=C–CH2 OH epoxidation 4.2 leukotriene antagonist S 0961 Ar-C=C–COOR dihydroxylation 4.3 paclitaxel Ar-C=C dihydroxylation 4.4 diltiazem (complex) Ar-CO–C=C-Ar epoxidation 4.5 SK&F 104353 (leukotriene antagonist) Ar-C=C dihydroxylation 4.6 LS 4416 (incontinence) Ar-CHO HCN addition 4.7 insecticide

Os-(DHQD)2 -PHAL

85

30

<1

[86]

Ti-dipeptide-molsieve 4 Å

96

20

∼1

[86]

Os-(DHQ)2 -PHAL

99

∼500

∼50–100

[90]

Os-cinchona

88

n.a.

Poly-l-alanine

96

Low

Os-(DHQ)2 -PHAL

95

Dipeptide

97

HMR/A ChiRex SKB SKB

Pharmacia/ Upjohn Sumitomo a For

Ton

Tof (h−1 )

Company

130 recycle 50

structures of starting materials, see Fig. 4, for structures of ligands, see Fig. 8.

Fig. 8. Various ligand and catalyst systems: short names and structures.

n.a. ∼0.1

Reference

[100] [101,102]

>20 dosing

[103]

∼12

[104,105]

H.U. Blaser et al. / Applied Catalysis A: General 221 (2001) 119–143

compounds, i.e., the catalytic systems are not only enantioselective but tolerant of many functional groups. The most prevalent catalyst metals are Ru (29), Rh (24) and Ti (7); only 7 of the 80 processes in Table 3 work with catalysts that are not noble or transition metal based. The most common chiral auxiliaries are diphosphines (14 biphep, 14 binap and analogs, 9 duphos, 8 ferrocenyl types, 10 various, respectively) and cinchona (8) and tartaric acid (7) derived compounds. This is also reflected in the commercial availability of auxiliaries (see Chapter 7). It is obvious that the optimal chiral auxiliary is not only determined by the chiral backbone (type or family) but also by the substituents of the coordinating groups. Therefore, modular ligand types such as the biphep or josiphos families with substituents that can easily be varied and tuned to the needs of a specific transformation have an inherent advantage (modular principle). The most often cited success factor was ligand design, i.e. the desired transformation was possible because either a new ligand type was found (designed) or because an existing type could be optimized by adapting the coordinating groups to the needs of the reaction (electronic and/or steric tuning). The choice of the right metal precursor and/or anion and the addition of promoters to the reaction solution were often decisive for high catalyst activity and productivity. Careful optimization of the reaction conditions (temperature, pressure, solvent, concentrations, etc.) and the ability to crystallize the product directly from the reaction solution with very high e.e. were mentioned several times to be very important for the commercial success of the process. The following critical factors often made the life difficult for many teams during process develop-

139

ment: sensitivity of the catalyst towards impurities (by-products in the starting material, oxygen, water, etc.); usually a strict purification protocol was sufficient to overcome these difficulties but in some cases the synthetic route of the substrate had to be altered. Sometimes, the stability of the ligand or catalyst and its productivity (ton) were critical; careful optimization was often successful to overcome this problem. Other critical issues mentioned: the need for high pressures or very low temperatures (expensive equipment), lack of commercial availability or difficult preparation of the ligand or catalyst, and problems with a patented ligand system. Surprisingly, despite the fact that most processes use a homogeneous catalyst, catalyst separation was mentioned only once to be a major problem! 6.2. Catalytic syntheses for (S)-naproxen (S)-naproxen is a large scale anti-inflammatory drug and is actually produced via the resolution of a racemate. For some time it was mentioned as one of the most attractive goals for asymmetric catalysis. Indeed, several catalytic syntheses have been developed for the synthesis of (S)-naproxen intermediates in recent years. However, despite some quite good catalytic results (see Table 13) it has become clear that the original resolution variant will be the optimal process for quite some time [51] (Fig. 5). Several reasons are responsible for this situation: • the resolution process developed by Syntex is almost ideal (Pope Peachy resolution) with an efficient racemization and recycling of the unwanted (R)-enantiomer (yield >95% of (S)-naproxen from the racemate) and the chiral auxiliary (recovery >98%);

Table 13 Processes for naproxena Company

Transformation development stage

Catalyst

e.e. (%)

Takasago Monsanto DuPont

C=C–COOH hydrogenation, bench scale process C=C–COOH hydrogenation, pilot process C=C hydrocyanation, bench scale process

Ru/binap Ru/binap Ni/glup2

97 97 90

U. Ottawa

C=C hydrocarboxylation first synthesis

Pd/binapo

91

a For

structures of starting materials/see Fig. 5, for structures of ligands, see Figs. 6 and 7. b Relative to Ni. c Relative to ligand.

Ton 3000 215 800b 5000c <20

Tof (h−1 )

Reference

300 18 ∼200

[107] [41,106] [108,109]

<1

[110]

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Table 14 Large scale ligands and chiral auxiliaries: short names (structure see Figs. 6–8), owner and/or supplier, patent status and availability Ligand (class)

Company

Rights, availability

Dipamp and analogs Deguphos and analogs Josiphos and analogs

NSC Technologies, Digital Specialty Chemicals Degussa-Hüls Ciba-Geigy/Novartis, Solvias (exclusive license)

Meduphos and analogs

DuPont, ChiroTech (exclusive license for pharma, flavor and fragrance use) ChiroTech (exclusive license) Merck, NSC Technologies, Takasago, Digital Specialty Chemicals, Oxford Asymmetry Roche, PPG-Sipsy (license) Chemi S.p.A. Bayer ChiRex ChiRex

Off patent, available in kg amounts Proprietary ligand Proprietary ligands, gram to multi kg amounts on request Proprietary ligands, commercial scale

Trost ligands [112] Binap and analogs Biphep and analogs [113] TMBTP and analogs [114–116] Bibfup Salen and analogs (DHQD)2 -PHAL, analogs and pseudoenantiomers (R)- and (S)-prolinol Cinchonidine, analogs and pseudoenantiomers tartaric acid and esters

Proprietary ligands commercial scale Proprietary ligand and/or synthesis of 100 kg scale immobilized ligand Proprietary ligands, commercial scale Proprietary ligands, commercial scale Proprietary ligand, commercial scale Proprietary ligands, produced at 100 kg scale Proprietary ligands, commercial scale

PPG-Sipsy Various suppliers

Commercial scale Commercial scale

Various suppliers

Commercial scale

• the starting materials used for the catalytic versions are much more expensive; US$ 20–25/kg for the vinyl and US$ 50/kg for the acrylic acid derivative, compared to ca. US$ 10/kg for methoxybromonaphthalene used in the Syntex process; • some of the catalytic transformations are not (yet) very effective and in all cases further enrichment would be necessary. 7. Large scale ligands and chiral auxiliaries Up to a few years ago, only a small number of ligands and chiral auxiliaries were available in the amounts needed for technical applications. In the meantime, the situation has improved significantly and today, technical quantities can be obtained (and the necessary licenses are granted) for all auxiliaries listed in Table 14. Of course prices and licensing conditions can vary significantly and must be negotiated on a case by case basis. 8. Some final comments As pointed out in some of the chapters above we were somewhat disappointed that only few enantioselective processes are used in actual production. There

is no doubt that besides the arguments given above, one reason for this low number is the fact that some companies do not publish actively on their production technologies. Another reason could be that we do not have access to (or did not make use of) certain publication channels. For example, just before sending our manuscript to the editor, it was mentioned in the footnote of a review that Hokko Chemical Industry Co. (Japan) is using the asymmetric phosphonylation of imines to produce ␣-amino phosphonic acids on an industrial scale [111]. Unfortunately, it was too late to get more information on this process for our review but there must be more cases like this. We are quite willing to write an up-date in due time and would appreciate information on new applications of enantioselective catalysts or of existing applications we have missed.

Acknowledgements We would like to thank our colleagues and friends in the industrial catalytic community to give advice and share some information during the writing of this review. Special thanks are due to our colleagues B. Pugin and A. Schnyder at Solvias for carefully reading the manuscript and to D. Ager (NSC Technologies),

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